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Parasympathetic nervous system: textbooks • Recommended (possible) literature 1/ Rang and Dale´s Pharmacology (2012) 2/ Mohr et al.: Color atlas of pharmacology (2011) 3/ Lippincot´s illustr. Pharmacology 4/ Simmons: Pharmacology illustr. review 2012 • Additional (optional) sources of information 1/ Goodman and Gilman´s, Pharmacological basis of therapeutics (2011) Nervous System • Central Nervous System (CNS) - Brain and spinal cord • Peripheral Nervous System (PNS) Autonomic Nervous System (ANS) – involuntary Somatic NS – voluntary /you can control e.g. sceletal muscles/ Autonomic Nervous System a/ sympathetic (thoracolumbal) b/ parasympathetic (craniosacral) Organization of the nervous system Nervous system Peripheral Nervous System Central Nervous System Efferent Division Afferent Division Autonomic System Somatic System Enteric Parasympathetic Sympathetic (according to Lippincott´s Pharmacology, 2006) Main functions of ANS • ANS acts on smooth muscles (contraction or relaxation) • ANS acts on glands • ANS controls (regulates) function of the heart, respiratory system, GI tract, bladder • ANS: involuntary influencing of physiological functions - we have little or no control on functions described above. • Circulation, breathing, digestion are regulated automatically, mechanism of feedback is applied ANS - 2 types of neurons: 1. Afferent (sensoric) - send impulses to the CNS for interpretation 2. Efferent - recieve impulses (information) from the brain & transmit from the spinal cord to the effector organ cells 2 branches - sympathetic & parasympathetic nervous system Efferent neurons of the autonomic system Cell body 1 Brainstem or spinal cord Preganglionic neuron Ganglionic transmitter 2 Postganglionic neuron Neuroeffector transmitter (according to Lippincott´s Pharmacology, 2006) Effector organ CENTRAL NERVOUS SYSTEM Acetylcholine (ACh) and noradrenaline (NA) as transmitters in the peripheral nervous system. ACh (nic) Skeletal muscle Somatic efferent system ACh (nic) NA Blood vessels etc. ACh (nic) ACh (mus) Sweat glands ACh (nic) Adrenal medulla ACh (mus) Salivary Parasympathetic glands etc. system ACh (nic) Sympathetic system (according to Rang HP, Dale MM et al.: Pharmacology, 2003) Summary of the neurotransmitters released and the types of receptors found within the autonomic and somatic nervous system. (according to Lippincott´s Pharmacology, 2006) Preganglionic neuron Ganglionic transmitter AUTONOMIC Sympathetic innervation Parasympathetic of adrenal medulla Sympathetic Acetylcholine Acetylcholine Nicotinic receptor Adrenal medulla Neuroeffector transmitter SOMATIC Acetylcholine Nicotinic receptor Nicotinic receptor Postganglionic neurons Epinephrine release Acetylcholine into the blood Norepinephrine Adrenergic receptor No ganglia Adrenergic receptor Effector organs Muscarinic receptor Acetylcholine Nicotinic receptor Striated muscle Somatic and autonomic nervous system Autonomic nervous system: mediators • nervous paths (tracts) lead to ganglions where information is transmitted via nicotinergic receptors • parasympathetic nerv. fibres release acetylcholine, that then acts on muscarine receptors: M1: brain, parietal cells of GIT M2: heart M3: smooth muscles and glands • sympathetic nerv. fibres release noradrenaline (exception sweat glands where acetylcholine is mediator) Effects of receptor activation on contraction of muscles • cardial inotropy • chronotropy of myocardial muscle (heart rate) • bronchi • excitation by beta 1 rcp and inhibition by M3 • excitation by beta 1 and inhibition by M2 • contraction M3 and dilatation by beta 2 Sympathetic and parasympathetic response of organs Parasympathetic response DRUGS INFLUENCING CHOLINERGIC RECEPTORS A/ Parasympathomimetics B/ Parasympatholytic drugs Cholinergic agonist drugs are termed parasympathomimetics, as they mimic the effects of acetylcholine in the parasympathetic system 1/ Direct acting parasympathomimetics bind directly to cholinergic receptors 2/ Indirect acting parasympathomimetics inhibit enzyme acetylcholinesterase Direct and indirect parasympathomimetic drugs Summary of cholinergic agonists Cholinergic agonists Direct acting Acetylcholine Bethanechol Carbachol Cevimeline Pilocarpine Indirect acting (reversible) Ambenomium Donepezil Edrophonium Galantamine Neostigmine Physostigmine Pyridostigmine Rivastigmine Tacrine Indirect acting (irreversible) Echothiophate Isoflurophate (according to Lippincott´s Pharmacology, 2006) Reactivation of acetyl-choline esterase Pralidoxime Cholinergic agonist drugs A/ Direct acting - act on the cholinergic receptors to activate a tissue response Side effects: Salivation, lacrimation Bronchospasm and bradycardia Diarrhea Contraindications Asthma Cardiac disease CHOLINERGIC RECEPTORS 2 types of cholinergic receptors 1. Muscarinic (G protein coupled) M1 in CNS M2 in heart M3 in smooth muscle and glands 2. Nicotinic (ligand gated ion channels) a/ muscle type, b/ neuronal subtypes • Neuromuscular junction • Autonomic ganglia and adrenal medulla (A cholinergic neuroeffector junction) Mediator acetylcholine - biochemistry • acts on muscarine and nicotine receptors • biochemical effect on M receptors: G protein, phospholipase C, Inositol triphosphates, increase of intracellular calcium and then physiological effect leading to contraction of smooth muscles or increase of secretion • degradation of acetylcholine is by enzyme acetylcholin-esterase Cholinergic mechanisms: parasympathomimetic drugs • muscarine agonists pilocarpine and carbachol 1/ pilocarpine is alkaloid that causes contraction of musculus ciliaris leading to relieving of Schlemm´s canal Indications: glaucoma with narrow angle, glaucoma attack, induction of miosis during intraocular procedures 2/ carbachol only for induction of miosis, not antiglaucomatic drug [Additional NOTE=not for learning before test about parasympathetic nerv. system : preferred antiglaucomatic drugs of first choice today are prostanoids (e.g. latanaprost) or selective betablockers like betaxolol Pilocarpine • lipophilic (tertiary nitrogen), central effect, an alkaloid from tropical American shrubs • Has effect on M receptors (partial agonist) and N effect (in ganglions) Use ophtalmology – antiglaucomatic Carbachol • Hydrophilic (N+), does not pass through the blood-brain barrier, higher ACHE resistance • Stimulates excretion + GIT Use: today as antiglaucomatic (rarely still in urinary retention and in GIT atonia) KI – GIT obstruction Methacholine, bethanechol Hydrophilic (N+), do not pass through the blood-brain barrier, higher ACHE resistance Use – almost not used any more (previously used for urinary retention, in GIT atonia, for increase of pancreatic functions, in glaucoma) KI – in GIT obstruction Indications of direct parasympathomimetic drugs rather few: • Rarely glaucoma (carbachol, pilocarpine) • rarely still in post-operative and neurogennic ileus, urine retention (bethanechol) B/ Indirect acting parasympathomimetic drugs inhibit acetylcholinesterase thereby increasing concentrations of acetylcholine and enhancing cholinergic function via activation of nicotinic and muscarinic receptors Representatives of reversible blockers of AChE 1/ fysostigmin 2/ neostigmin 3/ pyridostigmin 4/ donepezil, rivastigmine, galantamine Adverse effects of reversible inhibitors of cholinesterase • All of the side effects seen with direct parasympathomimetics + caused by increased nicotinic component • Possible side effects: 1/ Bradycardia and hypotension 2/ Bronchospasm / respiratory insufficiency = apply atropine that is parasympatholytic drug (3/ Convulsions, coma) Inhibitors of cholinesterase • Indications: 1/ Myasthenia gravis Neostigmin, pyridostigmine 2/ Relieving of effect of myorelaxant drugs used during surgical procedures (thus means post-operative atonia of GIT and urinary bladder) Neostigmine 3/ Atropine poisoning Physostigmine Arecoline misused in „betel“ nuts for its slight stimulatory effects chewing this stuff results in a red-brown discolouration of the mouth and staining of the teeth, and can lead to precancerous lesions and subsequently one or more varieties of oral cancer Symptoms of intoxication Extremely increased cholinergic activity, dependenig on the drug selectivity M-effects CNS stimulation, myosis, dyspnoe, bronchial hypersecretion and bronchoconstriction, diarrhoea, GIT hypermotility a secretion, hypotension, vasodilatation, bradycardia… N-effects – convulsions (CNS), increased blood pressure (adrenal N rec. stimulation) Indirect cholinomimetics - increase of ACH concentration on the cholinergic synapses (= not specific effect = M + N effects) - substrates for ACH synthesis (lecitine) - inhibitors of ACHE (= IACHE) - tertiary ammonium structures (NR3) - lipophilic – also centrally acting - quarternary ammonium cations (NR4+) - lipophilic – only peripherally acting physostigmine - lipophilic alkaloid from shrub Physostigma venenosum edrophonium 5-15 min (peripheral) physostigmine 0,5 – 2h (central) neostigmine 0,5 – 3h (peripheral) pyridostigmine 4-8h (peripheral) organophosphates DDT etc. - irreversible • Wikipedia • Reversible Inhibitors of Acetyl Choline Esterase Indications of indirect parasympathetics • Post-operative and neurogennic ileus, urine retention (neostigmine) • Myasthenia gravis – neostigmine, pyridostigmine • Alzheimer´s disease (demention, degeneration of cerebral cholinergic neurons) – rivastigmine, – donezepil – predominantly central effect – galantamine Irreversibile Acetyl Cholin Esterase Inhibitors = organophosphates Toxicology of organophosphates • herbicides, pesticides, DDT • Parathion primarily as insecticide • Nerve gas for biological war fare - tabun, sarin, soman (pass very fast through the skin) Poisonings! Use in pharmacotherapy – very rare scabies (malathione) Therapy of intoxication by organophosphates • • • • blocking of further absorption atropine – blocks muscarinic adverse effects mechanical ventilation AChE reactivators – pralidoxim, trimedoxim Parasympatholytic drugs A/ Tertiary amines (lipophilic): 1/ natural alkaloids in plants - Atropa belladonna, Datura stramonium, Hyosciamus niger – atropine, scopolamine… 2/ semi-synthetic analogues – homatropine B/ Quarternary ammonium structure (hydrophilic) N-butyl-scopolamine, Ipratropium, tiotropium Muscarinic antagonists direct parasympatholytic drugss Atropa belladona (nightshade deadly) Effects of Atropine Dose (mg) <0.5 Atropine effects reduced heart rate (bradycardia), reduced salivation, reduces sweating 1.0 increased heart rate, slight mydriasis, complete block of saliva production 2.0 tachycardia, mydriasis, reduced accomodation ability for near vision 5.0 intensified previous effects, swallowing disorders, tiredness, headache, urinary retention, constipation, dry and hot skin >10.0 further intensification of previous effects, rapid and slight pulse, blurred vision, scarlet red hot and dry skin, ataxia, restlessness, CNS excitation (hallucinations, delirium), coma Effects of Atropine • CNS 1/ antiemetic effect (scopolamine is used in pharmacotherapy of motion sickness) 2/ toxic doses of atropine - excitation, followed by delirium and coma • Eye = mydriasis - antimuscarinic effect on the sphincter smooth muscle of the iris - paralysis of the ciliary muscle of the eye resulting in a loss of accomodation = cycloplegia with accompanying mydriasis - atropine (5-7 days), homatropine (several hours) • Cardiovascular system - the heart rate may be slow initially or following a low dose (less than 0.5 mg) (result of central vagal stimulation + block of presynaptic M-autoreceptor inhibitory effects); as the muscarinic (M2) receptors on the SA node are blocked by higher concentrations of atropine, tachycardia results - at therapeutic doses – atropine has only mild effect on systemic blood pressure, but it causes vasodilatation of skin-vessel (red skin) – especially in high doses • GIT: - gastric and gut secretion is reduced at high doses, GI motility is reduced Smooth muscle: - GI contractions are reduced in amplitude and frequency, muscle tone is also reduced - biliary tract is relaxed - urinary bladder and ureter tone are reduced Respiratory system: - bronchodilatation occurs in the large bronchi - reduced secretion Sweat gland - secretion is reduced – body temperature is increased (fever in children) Possible therapeutic use of Atropine: 1/ Preanesthetic agent - to reduce salivary and respiratory secretions - „stabilizes“ n. vagus – prevention of vagal bradycardia and heart arrest 2/ Bradycardia – induced by antiarrythimcs or rather digoxine induced bradycardia) 3/ In toxicology - intoxications by organophosphate or mushroom (if muscarine is the toxic agent) Atropine is well distributed throughout the body including the CNS (IV=intravenous, IM=intramuscular, SC=subcutaneous, PO=peroral) Atropine adverse effects: - tachycardia, dry mouth, obstipation, blurred vision (mydriasis) urinary retention, increased body temperature (children), restlessness, desorientation - „atropine-like adverse effect“ are rather frequently seen as adverse effects after application of various drugs due to their insufficient receptor specifity (tricyclic antidepressants, typical antipsychotics etc.) Parasympatholytic indications I. Parkinson´s syndrom – dopaminergic drugs procyclidin) adjuvant therapy besides (biperiden, benzatropin, Kinetosis. – scolopamine (transcutaneous patch – effective for 24-48 h) In bradycardia - atropine Indications II. Ophtalmology Mydriasis for diagnostic purposes – homatropine (with shorter effect) is more usefull; locally (drops) Indications III. Gastrointestinal disturbances. At these indications quarternary ammonium bases are predominantly used. GIT spasmolytics for conservative cholelithiasis and urolithiasis therapy – N-buthyl-scopolamine, oxyphenonium, poldine, fenpiverin, otilium In GIT hypermotility – in diarrhoea (of travelers….) – mostly combination with non analgetic peripheral opioids (e.g. atropine with difenoxylate REASEC Indications IV. Asthma bronchiale therapy parasympatholytics induce bronchodilatation and attenuate lung secretion ipratropium ATROVENT, or in combination with sympathomimetic fenoterol (BERODUAL) Premedication for general anaesthesia – atropine, scopolamine - prevention of n.vagus stimulation (= perevention of laryngospasm, bronchospasm, bronchial hypersecretion – prevention of post-surgical atelectasis). BUT induces risk of urinary retention and gout hypomotility. Indications V. Therapy of IACHE overdose or intoxication (short- and medium-acting IACHE used in myasthenia gravis etc; irreversible IACHE –organophosphates). Atropine applied in high doses (1-2 mg i.v. for 5-15 min) until signs of antimuscarinic effect occure (dry mouth,mydriasis..) Mushrooms (Amanita muscaria) poisoning With fast onset (in 15-30min after consumption) – with muscarinic signs (nausea, vomiting, bradycardia, salivation, bronchoconstriction... In Amanita muscaria is an alkaloid – muscarine). Therapy with atropine (1-2 mg parenteral) Parasympatholytic intoxication Intoxication with tertiary amines: Central – CNS stimulation, excitation - hallucinations, convulsions, coma, central respiratory depression (coma) Peripheral – dry, warm/hot scarlatte red skin, dry mouth, no lacrimation, mydriasis, cycloplegia, tachycardia, low blood pressure, constipation, increased body temperature (fever in children) Therapy of intoxication - symptomatic (shock prevention, anticolvunsants diazepam) - IACHE (physostigmine - carefuly, it is rather toxic; neostigmine) - cooling of the patient Intoxication with quarternary ammonium bases: Peripheral antimuscarinic effects but partly also antagonism on N (ganglion) receptors (+ orthostatic hypotension due to the ganglioplegic effect …). Therapy - IACHE – neostigmine (=quarternary structure, only peripheral effects) - if necessary - possibly α1-sympathomimetic phenylephrine (against the low BP) Contraindications of parasympatholytic drugs - glaucoma (especially with closed ancle) - hyperthrophic prostate, serious prostatic hyperplasia (increased risk of urine retention) - paralytic ileus